Abstract: Objective. The aim of this study was to report the 30-day and 1-year outcomes and performance from the Portico Alternative Access study to obtain CE approval of the alternative access delivery system. Methods. The Portico Alternative Access study is a multicenter, prospective, non-randomized, investigational study (www.clinicaltrials.gov identifier, NCT03056573) describing 45 patients with severe symptomatic aortic valve stenosis (AS) treated with the self-expanding Portico device using subclavian/axillary access. Results. Forty-five subjects (81.7 ± 5.9 years; 57.8% female; Society of Thoracic Surgeons score, 5.4 ± 4.7%) with severe, symptomatic AS had a Portico bioprosthetic aortic valve implantation attempt via axillary/subclavian access. Implantation was successful in 97.8% of subjects. At 30 days, the rate of major vascular complications at the subclavian/axillary access site was 4.4%. All-cause mortality was 2.2% at 30 days and 4.4% at 1 year. Conclusion. The Portico transcatheter aortic valve can be safely delivered by axillary or subclavian access with high implant success rate and low complication rates.
J INVASIVE CARDIOL 2020;32(11):405-411. Epub 2020 August 10.
Key words: aortic stenosis, axillary access, subclavian access
For subjects with severe symptomatic aortic valve stenosis (AS) at increased risk for surgical aortic valve replacement (SAVR), transcatheter aortic valve implantation (TAVI) has become the treatment of choice.1-4
The Portico valve (Abbott Vascular) is a new-generation self-expanding TAVI device approved for transfemoral (TF) access TAVI, which has been shown to be safe with good hemodynamic performance and clinical outcomes.5,6 However, significant peripheral artery disease is common in subjects eligible for TAVI and may impede TF access.7 Alternatives are transarterial (subclavian/axillary artery or transcarotid), transcaval, and transthoracic access.8 It has been demonstrated that subclavian access is feasible and safe, with outcomes comparable to femoral access.9,10 Moreover, transapical (TA) as well as direct aortic (DA) access are associated with higher mortality compared with both TF and subclavian access.11 Subclavian/axillary access may therefore be considered a better alternative access in case of ineligible femoral anatomy.12
Off-label alternative access using the left subclavian/axillary artery for implantation of the Portico device has been shown to be feasible and safe.13 The Portico ALT study was designed to evaluate safety and performance of the Portico delivery system (Figure 1) using left subclavian/axillary artery or DA access to obtain CE approval of the alternative access delivery system.
Study design and oversight. The Portico Alternative Access study, a multicenter, prospective, non-randomized, investigational study (clinicaltrials.gov identifier, NCT03056573), included subclavian/axillary and transaortic access as separate arms of the study. We report the 30 day and 1-year results for the subclavian/axillary arm of the study.
The sponsor (Abbott Vascular) funded this pre-CE mark study, which was conducted at 8 centers in Europe. The centers function in compliance with the Declaration of Helsinki; approvals from local ethics committees and governing competent authorities were obtained. Each implanting physician had recent experience implanting Portico valves and experience implanting other devices via alternative access.
The study utilized an independent echocardiographic core laboratory (MedStar Health Research Institute, Washington D.C.). An independent computed tomography (CT) core laboratory (New York University School of Medicine, New York) was used as well as an independent clinical events committee (Cardiovascular Research Foundation, New York) for the assessment of all safety endpoints according to Valve Academic Research Consortium (VARC)-2 consensus.14
Subject eligibility. The subjects enrolled in this study had severe symptomatic native AS and were deemed at high surgical risk as defined by the Society of Thoracic Surgeons (STS) predicted risk of operative mortality score of at least 8% or documented heart team agreement of high risk for SAVR due to frailty or comorbidities.
In the opinion of the heart team, the preferred access for the subjects was subclavian or axillary access, considering specific anatomical considerations, other risk factors, as well as implanter and subject preference.
Prior to treatment, informed consent was obtained and subject data were reviewed by the subject selection committee (SSC) to confirm risk assessment, echocardiographic qualifications, and anatomical measurements. Subject anatomy was assessed via computed tomography (CT) imaging. The CTs were sent to the core laboratory to ensure suitability for the Portico device. The core lab assessment was provided to the SSC. If the SSC considered the subject ineligible for implant, the subject was withdrawn from the study.
Additional exclusion criteria included bicuspid aortic valve, subclavian/axillary arteries with severe calcification and/or tortuosity, left or right internal mammary artery functioning as a bypass graft precluding left or right subclavian/axillary access, or symptomatic coronary artery disease requiring revascularization.
TAVI and follow-up. Study subjects underwent TAVI via subclavian/axillary access using the CE-marked Portico transcatheter heart valve (THV), which is available in sizes 23 mm, 25 mm, 27 mm, and 29 mm and has been described in detail elsewhere.15
The devices under investigation in the Portico ALT study are the Portico TF (110 cm) and Alternative Access (65 cm) delivery system, which can both be used for alternative access delivery. The delivery systems have an outer diameter of 18 or 19 Fr to accommodate all Portico valve sizes and are designed to facilitate gradual, controlled deployment of the valve. The only difference between the delivery systems is the working length. Delivery system selection was left to the preference of the implanters.
After implant, subjects were followed at 30 days, 6 months, and 1 year post implant. Subjects without an implant attempt (ie, the delivery system was not introduced into the body) were withdrawn from the study. Echocardiographic evaluation was performed at baseline, at implantation, before discharge, at 30 days, at 6 months, and at 1 year post implant.
Endpoints. The primary study endpoint was the rate of major vascular complications (as defined by VARC-2) at 30 days. The secondary endpoints included prespecified rates of VARC-2 events and echocardiographic parameters at 30 days and 1 year, including all-cause and cardiovascular mortality, disabling and non-disabling stroke, life-threatening bleeding, acute kidney injury (AKI) requiring dialysis, composite of periprocedural encephalopathy, all stroke, and all transient ischemic attacks. Events were site reported and adjudicated by the clinical events committee. Other descriptive endpoints include acute device success, echocardiographic improvement, and functional improvement from baseline to 30 days and 1 year.
Valve hemodynamics were assessed at baseline, at discharge, and at subsequent visits following TAVI. The echocardiography core laboratory assessed left ventricular ejection fraction, mean aortic valve gradient, aortic valve area, total aortic regurgitation, PVL (PVL), and peak velocity at all time points. The implant depth was evaluated as stent protrusion into the left ventricular outflow tract (LVOT) as measured on angiography and was site reported.
Statistical analysis. Data collected at baseline and throughout the follow-up visits are summarized, using descriptive statistics, such as mean ± standard deviation for continuous variables, and frequency (percentage) for categorical variables. Data analysis was performed on a per-subject basis. The clinical events committee adjudicated adverse events and echocardiographic core laboratory measurements were used for the primary and secondary endpoint data.
Paired t-tests (echocardiographic data, 6-minute walk test) and the Wilcoxon signed ranked test (New York Heart Association [NYHA] functional class) were performed to compare the change from baseline to 30 days and 1 year for subjects who had a recorded value at both baseline and follow-up visits. Statistical significance was indicated by a P-value <.05. All statistical analyses were performed using SAS, version 9.4 (SAS Institute).
Between April 2017 and June 2018, a total of 45 out of 51 subjects enrolled underwent an implant attempt with the Portico device via subclavian/axillary access across 8 European sites. Six patients were excluded by the SSC for the following reasons: 4 patients were excluded for not meeting high surgical risk and/or frailty criteria, 1 patient was excluded because of anatomical criteria that were not met, and 1 patient was excluded because of emergency surgery within 30 days of the procedure. Enrolling sites were Rigshospitalet Copenhagen, Denmark; Heart Center Leipzig at University of Leipzig, Deutsches Herzzentrum Berlin and Universitatsklinikum Tubingen, Germany; Policlinico San Donato and Ospedale Niguarda Ca’Granda, Italy; Basel University Hospital, Switzerland; and RadboudUMC Nijmegen, The Netherlands.
Baseline characteristics. Mean age was 81.7 ± 5.9 years and 57.8% of subjects were women. The mean STS score was 5.4 ± 4.7, cut-off for at least 1 frailty assessment was met in 82.2%, and 80.0% of subjects were in NYHA class III or IV. Coronary artery disease was present in 71.1% of subjects at baseline, carotid artery disease in 17.8%, a history of atrial fibrillation in 35.6%, and peripheral artery disease in 48.9%. All subjects had severe, symptomatic AS with a mean aortic valve gradient of 41.0 ± 13.1 mm Hg and mean aortic valve area of 0.60 ± 0.2 cm² (Table 1).
Procedural characteristics. The majority of implants (n = 40; 88.9%) were performed under general anesthesia. All access was surgical. A sheath was used in 32 of 45 patients. Predilation was performed in 40 patients (88.9%). Valve resheathing and postdilation were performed in 51.1% and 33.3% of cases, respectively. Implanted valve sizes were 25 mm (n = 13; 29%), 27 mm (n = 18; 40%), and 29 mm (n = 14; 31%). Stent protrusion into the LVOT was 4.6 ± 2.2 mm. Mean procedure time, defined as access to delivery system removal, was 56.8 ± 28.4 minutes. Total implant time, defined as entry of the delivery system to its removal, was 15.8 ± 19.2 minutes. The 110 cm TF delivery system was used in 60% of patients, while the shorter 65 cm ALT system was used in 40% of patients (Table 2). All access closures were surgical. Implant success, defined as successful access, delivery, deployment of the valve, and retrieval of the delivery system, occurred in 44 of 45 patients (97.8%). There was no procedural mortality. One patient was converted to SAVR because of embolization of the Portico device into the ascending aorta, resulting in substantial PVL. Acute device success was defined as the absence of procedural mortality, and correct positioning of a single prosthetic valve into the correct anatomical location with adequate performance of the prosthesis (ie, mean gradient <20 mm Hg, peak velocity <3 m/s, and no moderate to severe PVL), and was achieved in 43 out of 45 subjects (95.6%). In addition to the patient converted to SAVR, 1 patient had a residual gradient >20 mm Hg with a peak velocity >3 m/s.
Primary endpoint. The primary endpoint of major vascular complication at the TAVI access site occurred in 2 patients (4.4%) (Table 3). One patient received a stent in the axillary/subclavian artery because of rupture of the axillary artery and 1 patient developed a hematoma at the access site with a significant hemoglobin drop, for which a transfusion was given. A major vascular complication at the non-access site occurred in 3 patients (6.7%). The minor vascular complication rate was 24.4%.
Secondary endpoint. All-cause mortality rates at 30 days and 1 year were 2.2% (n = 1) and 4.4% (n = 2), respectively. One patient (2.2%) died within 30 days of the index procedure from bacterial sepsis, and 1 patient died unexpectedly and unwitnessed within 1 year. There was no autopsy performed. By default, this death was adjudicated as cardiovascular in nature (Table 3).
No AKI was reported at 30 days. Life-threatening bleeding occurred in 2 patients (4.4%), and major and minor bleeding occurred in 5 patients (11.1%) and 9 patients (20%), respectively. There were no myocardial infarctions. Pacemaker implantation rate in patients with no previous permanent pacemaker in situ was 4.9% at 30 days and 7.3% at 1 year.
There were no transient ischemic attacks reported. Disabling and non-disabling stroke occurred in 1 patient (2.2%) and 4 patients (8.9%), respectively.
Functional and echocardiographic parameters significantly improved at 30 days and 1 year after TAVI implantation. Mean transvalvular aortic gradient decreased from 41.0 ± 13.1 mm Hg at baseline to 6.4 ± 2.7 mm Hg at 30 days and 6.5 ± 2.7 mm Hg at 1 year. Aortic valve area increased from 0.6 ± 0.2 cm2 at baseline to 1.7 ± 0.3 cm2 at 30 days and 1.8 ± 0.5 cm2 at 1 year. PVL was mild, trace, or absent in 97.2% of patients at 30 days post TAVI. PVL was ≥ moderate in 2.8% of patients at 30 days post TAVI and in 3.6% of patients at 1 year post TAVI. No severe PVL was reported. The majority of patients (80.0%) were in NYHA functional class III or IV at baseline, and this rate decreased to 11.9% at 30 days and to 5% at 1 year. In the paired data, 77.5% and 88% of patients improved at least 1 NYHA class between baseline and 30 days and 1 year post implant, respectively. Exercise capacity improved significantly, with 6-minute walk change from 207 ± 111 m at baseline to 271 ± 103 m at 30 days and 274 ± 95 m at 1 year in the paired dataset (P<.001).
In recent years, developments in TAVI devices and delivery catheter technology have led to smaller delivery systems. As a result, most TAVI patients can be treated using TF access. For the subset of patients with inadequate or hostile femoral anatomy, subclavian access is an alternative option.
Our study confirms that trans-subclavian or transaxillary implant of the Portico device is safe; implant and device success rates as well as safety outcomes are consistent with TF data. The primary endpoint of major vascular complication rate at the TAVI access site was comparable with data from the Portico TF-EU study.5 However, the overall major vascular complication rate was higher than expected, as a result of major vascular complications at the access site not used for THV delivery. This might reflect more advanced peripheral vascular disease at the level of the femoral arteries and the resulting higher risk for local complications. Transradial diagnostic access might be a viable alternative in these patients. Furthermore, the total major vascular complication rate was in line with a meta-analysis of 3519 patients including multiple access and TAVR valves, with a pooled estimate 30-day rate of 11.9% (95% confidence interval, 8.6%-16.4%).16 Similar findings were reported in a propensity-matched study of 202 patients treated with the Medtronic CoreValve using subclavian/axillary vs 202 patients using TF access. The major vascular complication rates were 11.9% vs 10.4%, respectively.17 This is in line with numerous other studies comparing alternative access with TF approach.16,18
Observed rates for cardiovascular and any-cause mortality, AKI, and myocardial infarction at 30 days were consistent with those found in the TF-EU cohort and earlier publications regarding the Portico valve using TF access5,6,19,20 as well as reported rates in earlier- and later-generation devices.3,11-13,21-23
The composite rate of any stroke (n = 5; 11.1%) was higher than expected, compared with the 7.5% for any stroke or transient ischemic attack in the subclavian group reported in the CoreValve Pivotal trial17 and a combined transient ischemic attack and/or stroke rate of 5% in the subclavian cohort of the United Kingdom TAVI registry.11 Therefore, a post hoc analysis was performed of the subjects with periprocedural stroke vs the whole cohort. Four out of 5 patients (80%) had a history of atrial fibrillation, as compared with 35.6% in the whole cohort (P=.047). Furthermore, patients with stroke tended to have more peripheral vascular disease (80% vs 45% in the whole cohort; P=.19) and longer procedure times (72.6 ± 22.5 minutes vs 54.9 ± 28.7 minutes in the whole cohort; P=.16).
Of all strokes, 2 non-disabling strokes might anatomically be related to the vertebral artery: in 1 patient the left vertebral artery (left subclavian artery access) and in 1 patient the right vertebral artery (right subclavian access; dissection of the right subclavian and vertebral artery). Vertebral ischemia might occur when a large-bore sheath is used in a relatively small subclavian artery, analogous to what is described for vascular complications. In a single-center cohort, a sheath to artery area ratio (defined as the sheath area divided by the minimal lumen area of the subclavian artery) of ≥1.63 was associated with vascular complications.24 Further research is necessary to determine whether high sheath to artery area ratio might be associated with vertebral ischemia.
Ultimately, the relatively small population size in our study might overestimate the real-life stroke rate. After all, the stroke rates in the larger Portico TF and transaxillary populations report lower rates for the composite of all stroke and transient ischemic attack, with stroke rates varying from 2.6% in over 900 patients25 to 5.5% in 120 patients in a subclavian cohort.13
Echocardiographic parameters show good hemodynamic performance and matching functional status improvements. Significant PVL as well as new permanent pacemaker implantation rates were in line with other second-generation valves26 and lower than rates published for the Portico valve in TF cohorts.5,19 Both findings might be the consequence of less protrusion of the stent frame into the LVOT, as the implant depth in the ALT was 4.6 mm as compared with 6.1 mm in the TF-EU cohort.5 Because of closer proximity of the access to the aortic valve, the subclavian/axillary access might provide the operator with more control and better angulation entering the LVOT, avoiding scraping of the anatomy closest to the conduction system. At baseline, none of the subjects had pre-existing right bundle-branch block, which might have contributed further to the low permanent pacemaker implantation rate.
Study limitations. The Portico ALT study is a non-randomized study designed to assess safety of the Portico delivery system using alternative subclavian/axillary access, which implies it provides no direct comparison with TF data or data concerning other valves.
The Portico ALT study focuses on 30-day and 1-year outcomes in a cohort of 45 subjects treated with the Portico valve and delivery system using axillary/subclavian access. The results of the Portico ALT cohort show that the Portico prosthesis can be implanted via the subclavian/axillary access with excellent success rate and acceptable safety profile, both using the TF and the ALT access delivery system. Safety endpoints as well as functional and echocardiographic measures are in line with earlier data on subclavian access for first- and second-generation TAVI devices and approach safety data for TF access.
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From the 1Universitair Medisch Centrum St. Radboud, Nijmegen, the Netherlands; 2Ospedale Niguarda Ca’Granda, Milan Italy; 3IRCCS Policlinico San Donato Milan, Milan, Italy; 4Heart Center Leipzig at University of Leipzig, Leipzig, Germany; 5Cardiology University Hospital Basel, University of Basel, Basel, Switzerland; 6Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; 7Deutsches Herzzentrum Berlin, Klinik fuer Herz-, Thorax- und Gefaesschirurgie, Berlin, Germany; 8Universitaetsklinikum Tuebingen, Universitaetsklinik fuer Thorax-, Herz- und Gefaesschirurgie, Tübingen, Germany; and 9Technische Universität Dresden, Universitätsklinik, Department of Internal Medicine and Cardiology, Heart Center Dresden, Dresden, Germany.
Funding: This study was funded by Abbott Vascular.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Bedogni reports personal fees from Medtronic, Abbott Vascular, Terumo, and Boston Scientific. Dr Bruschi reports consultant fees from Abbott Vascular and St. Jude. Dr Kempfert reports personal fees from Abbott Vascular, Edwards Lifesciences, and Medtronic. Dr Linke reports grant support from Novartis and Edwards Lifesciences; personal fees from Medtronic, Abbott Vascular, Edwards Lifesciences, Boston Scientific, Astra Zeneca, Novartis, Abiomed, Bayer, Pfizer, and Boehringer; stock options in Picardia, Transverse Medical, and Claret Medical. Dr van Wely reports proctor income from Abbott Vascular. Dr Jeger reports grant support from Boston Scientific and Edwards Lifesciences; non-financial support from Abbott Vascular, Medtronic, Boston Scientific, and Edwards Lifesciences. The remaining authors report no conflicts of interest regarding the content herein.
Manuscript accepted March 19, 2020.
Address for correspondence: Axel Linke, Technische Universität Dresden, Universitätsklinik, Department of Internal Medicine and Cardiology, Heart Center Dresden, Fetscherstraße 76, 01307 Dresden, Germany. Email: Marleen.firstname.lastname@example.org